Presentation on theme: "CELL-MEDIATED SPECIFIC IMMUNITY. Regulation: is mediated by cytokines and cell-to-cell contact B cells and immunoglobulin production T cell cytotoxicity."— Presentation transcript:
CELL-MEDIATED SPECIFIC IMMUNITY
Regulation: is mediated by cytokines and cell-to-cell contact B cells and immunoglobulin production T cell cytotoxicity natural killer cells (NK) cell chemotaxis Effector function: T cell mediated specific cytotoxicity T CELLS: PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM
DIFFERENTIATION OF T CELLS plays in thymus cell-to-cell contact with epithelial and dendritic cells humoral factors thymic hormones: small peptides thymosine, thymopoetin immunomodulation
THE MOST IMPORTANT EVENTS IN INTRATHYMIC DEVELOPMENT OF T CELLS T cells in thymus: proliferate and differentiate (functional cell-surface molecules) rearrange genetic information coding TcR express TcR heterodimers on the surface induction of self tolerance is generated
DIFFERENTIATION OF T CELLS migration in to thymus is non-random (homing) humoral chemotactic factors (chemokines) specific surface interactions differentiation is characterized by: migration from subcapsular sinus into medulla proliferation morfological changes changes in surface molecules majority of thymocytes is dying by apoptosis due to differentiation failure
MEMBRANE MOLECULES OF T CELLS receptors for antigen: heterodimers TcR, TcR pan T cells: expressed on all T cells (CD7, CD2, CD3) subpopulations: helper inducer T cells CD4 + suppressor cytotoxic T cells CD8 + other subsets: thymocytes (CD1)
SURFACE MOLECULES OF T CELLS : CD69 T cell CD3 TcR CD2 ICAM1 adhesion molecules HLA II. IL-2R activation molecules CD28 costimulatory molecules receptors for cytokines accessory molecules recognition of Ag CD25 CD4 (CD8) CTLA 4
RECEPTORS FOR ANTIGEN ON T CELLS (TcR) are surface molecules responsible for specific recognition of antigen which is processed in APC and presented in association with self HLA I (II) molecules heterodimer, member of immunoglobuline family (domain) pre TcR is premature form of TcR found on thymocytes majority of mature T cells express heterodimer minority of mature T cells express heterodimer
RECEPTORS FOR ANTIGEN ON T CELLS (TcR) variable TcR domain: unique amino acids composition in antigen-combining site weak chemical forces between binding site of TcR and antigenic peptide are formed
RECEPTOR FOR ANTIGEN ON T CELLS (TcR) S S S S S S S S TcR SS DNA C C V V DD J J
enormous number of T cells with different TcRs approx. 1x10 16 different TcR specifities in theory overloading of theoretical coding capacity of genom genetic information for TcR is specifically organised into gene segments genetic information for TcR is specifically processed (gene rearrangement) BASIC IMMUNOLOGICAL REPERTOIR OF TcR
REARRANGEMENT OF TcR GENE SEGMENTS 5´ 3´ V1V1 V2V2 VnVn D1D1 D2D2 DnDn J1J1 JnJn C 5´3´ V1V1 D3D3 J1J1 C DNA mRNA NC V3 J1 J2 RAG -1,2 J3 RAG -1,2 V4 Vn V1 V2 D1D1 D2D2 D3D3 J1J1 JnJn J2J2 JnJn rearrangement n = hundredsn = tens n = single transcription splicing translation VARIABILECONSTANT TcR chain
uncorrected joining of V (D) gene segments to J genes random insertion of nucleotides in to D-J region (enzyme TdT) unsuccesful rearrangement induces apoptosis of thymocytes BASIC REPERTOIR OF TcR IS INCREASED BY
TcR are expressed on cell in association with CD3 complex - TcR: small cytoplasmic part - CD3: trimolecular complex - noncovalently associated with TcR - transmission of activation signals in to cell - ITAM: Immunoreceptor Tyrosin-based Activation Motif phosphorylation of tyrosine (kinases) - CD4: lck kinase - costimulatory interactions: - CD28, CTLA-4 B7.1, B7.2 - critical level of activation signals is necessary to start T cell activation and clonal expansion EXPRESSION OF TcR
S S S S S S S S TcR SS V C S S S S S S S S ITAMITAM ITAMITAM CD 3 COMPLEX TcR - CD 3 COMPLEX ON T CELLS ITAM: Immunoreceptor Tyrosin-based Activation Motif
IMMUNE RECOGNITION ACTIVATION OF T CELL clonal expansion effector functions anergy apoptosis no effect Krejsek, 2004 T cell
INTERACTIONS BETWEEN T CELL AND APC CELL exogenous antigen endogenous antigen APC Tcell adhesion interaction ICAM-1 LFA-1 accessory interaction LFA-3 CD2 costimulation B7 CD28 HLA II TcR CD4 CD3 lck clonal expansion processing: peptide+ HLA I processing : peptide+ HLA II PRESENTATION STAT P P JAK signal II cytokines signal I transcription factors
T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN CONTEXT Tcells Bcells migration NK COSTIMULATORY INTERACTIONS context (danger patterns) -accessory interactions - cytokine microenvironment = II nd signal COSTIMULATORY INTERACTIONS context (danger patterns) -accessory interactions - cytokine microenvironment = II nd signal COGNITIVE INTERACTION : TcR, HLA-Ag, CD4 (CD8) = I st signal COGNITIVE INTERACTION : TcR, HLA-Ag, CD4 (CD8) = I st signal activation of T cells activation of T cells clonal expansion effector and regulatory functions
INDUCTION OF SELF TOLERANCE Basic immunological repertoir of TcRs is generated: randomly in advance without presence of Ags in embryonal life in thymus Basic immunological repertoir of TcRs includes clones with high probability of self-recognition (autoreactive) of T cells. Autoreactive clones of T cells have to be eliminated by selection.
SELECTION: POSITIVE SELECTION : T cell clones are tested for affinity (not recognition) of self HLA I, II molecules NO AFFINITY: SELECTION (DELETION) NEGATIVE SELECTION : T cell clones are tested for recognition of self molecules quantitative phenomena EFFECTIVE RECOGNITION: SELECTION (DELETION) Mature T cell: toleration of self recognition of non-self.
REGULATORY AND EFFECTOR SUBSETS OF T CELLS mature T cells (TH0) differentiate into functionally distinct subsets after antigen stimulation TH1 TH2 presentation of microbial. Ag (LPS, CpG, lipoteichoic a.) dendritic c., macrophage, intensive, long term IL-12 presentation of environmental. Ag nonmicrobial origin (allergens) B-cells, weak, short term IL-4 TH0 INHIBITION INF IL-4 TH1 TH2 TH1 TH2 cytotoxic reactivity antibodies production, isotypic switching
protective immunity against particular agent could be either TH1 or TH2 driven there are subsequent waves of both TH1 and TH2 reactivities in the course of natural infections implication for vaccine development PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTION IS REGULATED BY OPTIMAL BALANCE BETWEEN TH1 AND TH2 SUBSETS.
IMMUNOPATHOLOGY: predominant TH pattern could be delineated for particular immunopathological diseases (TH1 multiple sclerosis,TH2 atopy) the immunopathology –driven inflammation is regulated by the mix of both subsets activities